Type 1 diabetes affects more than one million individuals, mostly children and young adults, in the United States and many more worldwide. It occurs in genetically predisposed individuals as a consequence of immune-mediated destruction of the pancreatic islet insulin-secreting beta cells. The present treatment for Type 1 diabetes, when implemented properly, can delay or prevent the long-term complications of diabetes (i.e., blindness, renal failure, and amputation). However, proper diabetes treatment is quite difficult to do, expensive, and very invasive to the diabetic patient's lifestyle. Diabetes is also a major factor in health care costs. Is it possible to prevent Type 1 diabetes or to preserve insulin secretion once diabetes has develped? Several immune interventions have been tried in genetically susceptible individuals without success. Other trials have been attempted to intervene early in the course of Type 1 diabetes, in order to preserve beta cell function. These immune interventions using drugs with potential toxicity have failed. Thus, the identification of agents which either prevent the disease or slow its progression would result in major health care cost savings and reduce complications related to diabetes in addition to the huge individual savings in terms of not having the disease. Our long-term goal is to prevent the development of Type 1 diabetes through the use of innovative based therapies designed to prevent the development of the disease in genetically predisposed individuals. The objectives of this application, in pursuit of that goal and in response to the RFA, is completion of the TrialNet protocols and to continue to develop and test innovative interventions to prevent or slow the progression of Type 1 diabetes. One such innovative approach to slow the progression of Type 1 diabetes is our proposed protocol, "Pioglitazone Preserves Insulin Secretion in Type 1 Diabetes." The proposed work is innovative because it utilitizes a drug that is in wide spread use with low toxicity yet has immunomodulation and anti- inflamatory properties. We have also designed a series of mechanistic studies to examine whether the anti-inflammatory properties of the drug operate by influencing regulatory T-cells. PUBLIC HEALTH RELEVANCE: The significance of this research is that the prevention of type 1 diabetes will save millions of dollars and enormous human suffering. The identification of agents which either prevent the disease or slow its progression would result in major health care cost savings and reduce complications related to diabetes in addition to the huge individual savings in terms of not having the disease.